Inhibitory Effects of Mas-Related Gene C Receptor on Chronic Morphine-Induced Spinal Glial Activation in Rats

Glial activation plays a pivotal role in morphine tolerance. This study investigated effects of Mas-related gene (Mrg) C receptor on morphine-induced activation of microglia and astrocytes in the spinal cord and its underlying mechanisms. Intrathecal administration of morphine (20 μg, daily) for 6 days induced a great decline in morphine antinociception and increased expression of glial fibrillary acidic protein and OX-42 in the spinal dorsal horn. These changes were greatly attenuated by the intermittent coinjection of bovine adrenal medulla 8-22 (BAM8-22, 1 nmol), a specific agonist of MrgC receptor. These modulatory effects were accompanied by the reduction of P2X₄ and interleukin-1β expressions in the spinal dorsal horn. Chronic morphine increased the expression of fractalkine in medium- and small-sized neurons of dorsal root ganglia (DRG). Treatment with BAM8-22 inhibited these changes as well as an increase in Toll-like receptor 4 (TLR4) protein in DRG. Chronic treatment of DRG explant cultures with morphine (3.3 μM, 5 days) increased the levels of fractalkine mRNA. Application of BAM8-22 (10 nM) for 60 minutes completely blocked the increase of fractalkine mRNA induced by morphine. Our findings indicate that the inhibition of morphine tolerance by MrgC receptor was associated with the modulation of astrocytes and microglia in the spinal dorsal horn and fractalkine and TLR4 expressions in DRG. As MrgC receptor is exclusively located in DRG, intermittent combination of MrgC receptor agonist could be a promising adjunct with limited side effects for chronic use of opiates.